Insulin glargine

Systematic (IUPAC) name
Recombinant human insulin
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a600027
Pregnancy cat.	C (US)
Legal status	POM (UK) ℞-only (US)
Routes	Subcutaneous
Identifiers
CAS number	160337-95-1 Y
ATC code	A10AE04
DrugBank	DB00047
UNII	2ZM8CX04RZ N
KEGG	D03250 Y
Chemical data
Formula	C267H404N72O78S6
Mol. mass	6063 g/mol
N (what is this?)  (verify)

Insulin glargine, marketed by Sanofi-Aventis under the name Lantus, is a long-acting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. It consists of microcrystals that slowly release insulin, giving a long duration of action of 18 to 26 hours, with a "peakless" profile (according to the Lantus package insert). Pharmacokinetically, it resembles basal insulin secretion of non-diabetic pancreatic beta cells. Sometimes, in type 2 diabetes and in combination with a short acting sulfonylurea (drugs which stimulate the pancreas to make more insulin), it can offer moderate control of serum glucose levels. In the absence of endogenous insulin—Type 1 diabetes, depleted type two (in some cases) or latent autoimmune diabetes of adults in late stage—Lantus needs the support of fast acting insulin taken with food to reduce the effect of prandially derived glucose.

Benefit[link]

When standard NPH is administered at night, its peak of action can coincide with the lower serum glucose levels associated with nocturnal metabolism potentially setting the stage for nocturnal hypoglycaemia. Lantus is associated with a lower risk of nocturnal hypoglycaemia.

Pharmacological specifications[link]

Mechanism of action (pharmacodynamics)[link]

Insulin glargine have substitution of glycine for asparagine at A21 and two arginines added to the carboxy terminal of B chain. The arginine amino acids shift the isoelectric point from a pH of 5.4 to 6.7, making the molecule more soluble at an acidic pH, allowing for the subcutaneous injection of a clear solution. The asparagine substitution prevents deamidization of the acid-sensitive glycine at acidic pH. In the neutral subcutaneous space, higher-order aggregates form, resulting in a slow, peakless dissolution and absorption of insulin from the site of injection.^[1] It can achieve a peakless level for at least 24 hours.

Acceptance and repartition in the body (pharmacokinetic)[link]

Lantus is formulated at an acidic pH 4, where it is completely water soluble. After subcutaneous injection of the acidic solute (which can cause discomfort and a stinging sensation), when a physiologic pH (approximately 7.4) is achieved the increase in pH causes the insulin to come out of solution resulting in the formation of higher order aggregates of insulin hexamers. The higher order aggregation slows the dissociation of the hexamers into insulin monomers, the functional and physiologically active unit of insulin. This gradual process ensures that small amounts of Lantus are released into the body continuously, giving an almost peakless profile.

Usage[link]

Mixing with other insulin preparations[link]

Unlike some other longer-acting insulins, Lantus must not be diluted or mixed with other insulin or solution in the same syringe.^[2] However, this restriction has been successfully challenged in trials conducted by Kaplan, Rodriguez, Smith, Haymond, and Heptulla of Texas Children's Hospital.^[3]

Other information[link]

Development[link]

The development of Lantus was conducted at Sanofi-Aventis's biotechnology competence center in Frankfurt-Höchst. Sanofi supplies the product to over 100 countries and more than 3,5 million patients worldwide. This makes Lantus Germany's largest and most important export pharmaceutical product. Sanofi-Aventis increased its turn-over with Lantus around 28% to 2,45 Billion €, therefrom 130 Million € in Germany, where approx. 1,8 Mio. people with diabetes applied this preparation. In 2007 Lantus ranked place 15 on top-selling pharmaceutical products in Germany.

The investment in the production of Lantus and insulin-pen-manufacturing at the location Frankfurt-Höchst lied at 700 Mio. €. In 2008 a new manufacturing plant was established for further insulin-pen with an investment sum of 150 Mio. €. At Sanofi-Aventis the production of Lantus created 3000 jobs in Berlin and Frankfurt-Höchst.

On June 9, 2000 the European Commission approbated Sanofi-Aventis Germany Ltd. the launching of Lantus in the entire European Union. The admission was prolonged on June 9, 2005.^[4]

Advantages[link]

International clinical studies have confirmed the advantages of insulin glargine in the treatment of heavy hypoglycaemia compared to standard NPH insulin. Insulin glargine reduces the risk of severe nocturnal hypoglycaemia. Extensive clinical studies (ACCORD) have confirmed the higher risk of mortality with higher incidence of severe hypoglycaemia.^[5][6] A comparison trial of insulin detemir and glargine proved that subjects randomized to detemir used slightly higher daily insulin doses, but gained less weight on average than glargine-treated subjects.^[7] Other systematic reviews corroborate the results of benefit of insulin glargine regarding lower incidence of severe hypoglycaemia.^[8]

On June 13, 2009, Diabetologia, the journal of European Association for the Study of Diabetes (EASD), published the results of a 5 year long-term observational, retrospective analysis. During the study no other safety issues, such as unexpected adverse events for either insulin emerged. However, insulin glargine was associated with a lower incidence of severe hypoglycaemia compared with NPH insulin.^[9]

Possible cancer link[link]

On June 26, 2009, Diabetologia published the results of four large-scale registry studies from Sweden, Germany, Scotland and the rest of the UK. The German study, of around 127,000 insulin-treated patients from an insurance database, suggested a possible link between insulin glargine (Lantus) and increased risk of developing cancer.^[10] The risk of cancer was dose-dependent, with those taking higher doses of Lantus apparently at increased risk.^[11] Whilst the authors stressed the limitations of the study and recommended that patients prescribed Lantus continue to take the drug, the results led to the EASD making "an urgent call for more research into a possible link between use of insulin glargine (an insulin analogue, brand name Lantus) and increased risk of cancer."^[12]

The European Medicines Agency (EMEA) responded, stating that the results of the four studies were inconsistent, and that a relationship between insulin glargine and cancer could neither be confirmed nor excluded.^[13] They announced that they would undertake further detailed assessment of the studies’ results and any other relevant information, including several potential confounding factors that had not been fully taken into account by the studies. Patients being treated with insulin glargine were advised to continue their treatment as normal. ^[13] The following month, the EMEA reported back, concluding that "the available data does not provide a cause for concern and that changes to the prescribing advice are therefore not necessary.”^[14]

The American Diabetes Association (ADA) also responded to the Diabetologia report, describing the published registry studies as “conflicting and confusing” and “inconclusive”. They advised patients against discontinuing Lantus and warned against "over-reaction".^[15]

New study confirms cancer link[link]

Type 1 diabetics who used Lantus had a 2.9-fold greater chance of cancer, while those who took the generic drug metformin had an 8 percent lower risk, according to a study presented on 9 December 2011 at the San Antonio Breast Cancer Symposium. Researchers examined medical records of 23,266 patients in southern Sweden.

The researchers were unable to identify which types of cancer were most common among Lantus users, said Hakan Olsson, lead researcher and professor of oncology at Lund University. They plan to follow the patients, and investigate different forms of treatment for Type 1 diabetes, including Novo Nordisk A/S’s long- acting insulin Levemir, to tease out any differences, he said.

“Women should be aware that diabetes and breast cancer may be related,” Olsson said in a telephone interview. “The diabetes itself could play a role in the development of cancer and now data is emerging that drug therapy may also be important in relation to cancer.” ^[16]

References[link]

1. ^ Bolli, G. et. al. (1999). "Insulin analogues and their potential in the management of diabetes mellitus.". Diabetologia 42 (10): 1151–1167. http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=10525654&retmode=ref&cmd=prlinks. 
2. ^ American Diabetes Association (2003). "Position statement: Insulin administration". Diabetes Care 26 (Suppl. 1): 121–124. 
3. ^ Kaplan, W.; et al. (2004). "Effects of Mixing Glargine and Short-Acting Insulin Analogs on Glucose Control". Diabetes Care 27 (11): 2739–2740. DOI:10.2337/diacare.27.11.2739. PMID 15505016. 
4. ^ EPAR Lantus, German summary of admission report of EMEA (PDF)
5. ^ [1], Action to Control Cardiovascular Risk in Diabetes (ACCORD), Trial , June 6, 2008
6. ^ [2], Effects of Intensive Glucose Lowering in Type 2 Diabetes
7. ^ L. Raymond Reynolds, MD, FACP, FACE, ECNU (January 2010). "Comparing Insulins Detemir and Glargine in Type 2 Diabetes: More Similarities than Differences". Postgraduate Medicine 122 (1): 201–203. DOI:10.3810/pgm.2010.01.2116. PMID 20107306. http://www.postgradmed.com/index.php?article=2116. 
8. ^ Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H (February 2009). "Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis". CMAJ 180 (4): 385–97. DOI:10.1503/cmaj.081041. PMC 2638025. PMID 19221352. http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=19221352. 
9. ^ Rosenstock J, Fonseca V, McGill JB, Riddle M, Hallé JP, Hramiak I, Johnston P, Davis M. (13 June 2009). "Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study". Diabetologia 52 (9): 1778–88. DOI:10.1007/s00125-009-1415-7. PMC 2723680. PMID 19526210. http://www.springerlink.com/content/c4352jj00640558p/fulltext.pdf. 
10. ^ Hemkens LG et al (26 June 2009). "Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study". Diabetologia 52 (9): 1732–44. DOI:10.1007/s00125-009-1418-4. PMC 2723679. PMID 19565214. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2723679. 
11. ^ http://webcast.easd.org/press/glargine/transcript.htm
12. ^ http://www.diabetologia-journal.org/cancer.html
13. ^ ^{a b} [3] European Medicines Agency update on safety of insulin glargine, June 29, 2009
14. ^ [4] European Medicines Agency update on safety of insulin glargine, July 23, 2009
15. ^ [5] Statement from the American Diabetes Association Related to Studies Published in 'Diabetologia', June 26, 2009
16. ^ Article at www.businessweek.com, 'Sanofi’s Lantus Doubled Risk of Cancer in Study of Diabetics', by Michelle Fay Cortez, December 09, 2011.

External links[link]

• Insulin glargine - MedlinePlus
• Lantus website (Sanofi-Aventis)
• U.S. National Library of Medicine: Drug Information Portal - Insulin glargine
• Comparing Insulins Detemir and Glargine in Type 2 Diabetes: More Similarities than Differences